Cortistatin is a neuropeptide that has a strong similarity to somatostatin and selectively induces slow wave sleep, presumably by antagonizing the effects of the neurotransmitter acetylcholine on cortical excitability. Preprocortistatin is exclusively expressed in a subset of cortical and hippocampal interneurons that utilize GABA as their neurotransmitter. These features and others make cortistatin a sleep factor that may have a major role in cortical synchronization and the maintenance of slow wave sleep. During the period of the grant entitled "Neuropeptide cortistatin and sleep," three animal models have been generated, cortistatin-overexpressing transgenic mice, cortistatin systemic knock-out and cortistatin conditional knock-out mice. In this competitive renewal, cortistatin-deficient (cst ko) mice will be studied using anatomical, behavioral, electrophysiological and molecular methods. Cst ko mice will be analyzed for anatomical and developmental abnormalities. Since the activity of cortical interneurons is important for the maintenance of slow wave sleep electrophysiological measures of excitability will be recorded in hippocampal slices of cst ko mice. The consequences of cortistatin mis-expression on sleep- and circadian-related processes will be studied in mice with null mutations in the cortistatin and somatostatin genes. Finally, the molecular consequences of cortistatin and somatostatin deficiency will be studied using oligonucleotide-based microarrays and alternatively with differential display methods. Completion of this proposal will unambiguously address the role of cortistatin and somatostatin peptides in sleep regulation, delineate their signaling pathway and analyze possible cross-talk or genetic compensation, which may yield therapeutic applications and a better understanding of human sleep disorders in which cortical activity is affected.